Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis

Abstract

Amyloid β-peptide (Aβ) is a major constituent of senile plaques in Alzheimer's disease (AD). Neurotoxicity results from the conformational transition of Aβ from random-coil to β-sheet and its oligomerization. Among a series of ionic compounds able to interact with soluble Aβ, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemed™) was found to maintain Aβ in a non-fibrillar form, to decrease Aβ₄₂-induced cell death in neuronal cell cultures, and to inhibit amyloid deposition. Tramiprosate crosses the murine blood-brain barrier (BBB) to exert its activity. Treatment of TgCRND8 mice with Tramiprosate resulted in significant reduction (∼30%) in the brain amyloid plaque load and a significant decrease in the cerebral levels of soluble and insoluble Aβ₄₀ and Aβ₄₂ (∼20–30%). A dose-dependent reduction (up to 60%) of plasma Aβ levels was also observed, suggesting that Tramiprosate influences the central pool of Aβ, changing either its efflux or its metabolism in the brain. We propose that Tramiprosate, which targets soluble Aβ, represents a new and promising therapeutic class of drugs for the treatment of AD.

Introduction

The presence of amyloid deposits in the brain is one of the major histopathological characteristics of Alzheimer's disease (AD) [55]. The amyloid cascade hypothesis proposes that the amyloid β-peptide (Aβ), a major component of amyloid plaques, is causally related to AD neurodegeneration and is a promising therapeutic target for disease-modifying treatment [21], [22].

The Aβ peptide is produced from the sequential post-translational processing of the amyloid precursor protein (APP) by β- and γ-secretases [41]. Familial AD (FAD) mutations within the human APP gene have been linked to AD [18]. These mutations appear to cause the disease by increasing the processing of APP thereby augmenting the total levels of Aβ or specifically favoring the production of Aβ₄₂[8], [45], [46]. The more hydrophobic Aβ₄₂ peptide has been shown to be more fibrillogenic in vitro, to favor the formation of assembly states thought to mediate neurotoxicity, and to facilitate the process of amyloid plaque deposition [2], [3], [19], [25], [51]. Other FAD mutations have been linked to the presenilin (PSEN) 1 and 2 genes and appear to favor the production of Aβ₄₂ peptides [31], [40], [47], [48]. Importantly, mice harboring APP and/or PSEN1/PSEN2 with FAD mutation(s) show a progressive increase in Aβ levels and develop pathological [11], [14] and behavioral changes reminiscent of those observed in AD [5], [10], [23].

Current anti-amyloid strategies are aimed at blocking the processing of APP by targeting the β- or γ-secretase activities, the formation of amyloid fibrils, and amyloid-associated neurotoxicity [28]. Other recent approaches have attempted to upregulate either the processing of APP by the α-secretase (non-amyloidogenic pathway) or the clearance of the Aβ peptides and associated amyloid deposits from the brain [6]. Anti-inflammatory agents with an effect on APP processing are also under investigation [32], [49], [54]. Several other approaches have been shown to reduce the amyloid load in transgenic animal models [1], [9], [42] with a favorable effect on cognitive function [4], [24], [33], [37].

Proteoglycans, a prominent constituent of amyloid deposits, are implicated in amyloid fibril formation [20]. The sulfated glycosaminoglycans (GAGs), a component of the proteoglycans, contribute to fibrillogenesis by promoting the transition of Aβ from a random-coil to a β-sheet rich conformation and protecting the fibrillar protein from proteolysis [7], [20], [26], [27], [50]. We have screened a series of low-molecular weight (LMW) molecules that mimic the ionic properties required for the binding of GAGs to Aβ. Our previous work revealed that such LMW molecules cross the blood-brain barrier (BBB), are anti-fibrillogenic, and diminish Aβ-induced toxicity in SH-SY5Y neuronal cell cultures [15].

Here we report that a specific ionic compound, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemed™), binds preferentially to soluble Aβ, maintains Aβ in a random-coil/α-helical rich conformation, and reduces the amyloid burden in TgCRND8 transgenic mice that develop early-onset, aggressive brain amyloidosis [5], [24]. Targeting soluble Aβ in vivo resulted in a dose-dependent reduction in both the soluble and fibrillar amyloid burden in these mice. This new class of drug represented by Tramiprosate holds promise for the treatment of AD.